The ability of phencyclidine (PCP) to reproduce positive and negative symptoms of schizophrenia, coupled with its ability to block the N-methyI-D-aspartate (NMDA) subtype of glutamate receptor, is an important part of the "hypoglutamatergic" hypothesis of this disease. Postmortem analysis of schizophrenic brains and epidemiological, genetic and developmental studies suggest that schizophrenia is very likely the result of developmental deficits that occur at critical periods of neuro- and synaptogenesis in the frontal cortex and other key areas, including the hippocampus. This laboratory developed a rodent model of schizophrenia in which perinatal subchronic administration of PCP resulted in selective apoptosis of cortical neurons and subsequent deficits in behaviors related to human schizophrenia. Apoptosis and behavioral deficits were blocked by treatment with the atypical antipsychotic, olanzapine. Neither the biochemical basis of cortical cell death, nor the basis cortical selectivity is understood. The proposed project will use a newly developed model in which in vitro treatment of corticostriatal slices in organotypic culture with PCP results in cortical, but not striatal, neuronal death. Two hypotheses will be used to direct Specific Aims designed 1) to determine the precise role of upregulation of NMDA receptor subunits in PCP-induced cortical neurotoxicity, 2) to determine the potential role of superoxide and nitric oxide formation, altered phosphorylation of the I-kappaB inhibitory protein and its regulation of NF-kappaB nuclear translocation, altered Bcl-2 family proteins, mitochondrial release of cytochrome c and activation of caspase-3 in PCP-induced neurotoxicity, and 3) to determine the role of altering neuronal glutamate release by activation of metabotropic glutamate receptors in PCP-mediated neurotoxicity. Additional experiments will test the third hypothesis that the relatively protected status of the striatum is due to the activation of a survival pathway involving activation of the cAMP response element (CRE) by phosphorylation of the CRE binding protein (CREB) and the CREB binding protein (CPB) through intracellular Ca2+ activation of CaM kinase IV and the Ras/MEK/ERK pathway. Activation and inhibition of key players in these pathways, as well as downstream activation of brain derived neurotrophic factor (BDNF) will be tested for their involvement in protecting the striatum and hippocampus from the toxic effect of PCP. The potential role of CREB dephosphorylation as a result of over activation of NMDA receptors will also be assessed in the neurotoxicity of PCP treatment.